Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations
Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations
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全基因组关联研究和功能分析的荟萃分析破译中国人群胃癌易感基因
DOI：
10.1136/gutjnl-2019-318760
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发表时间：
2020-04-01
期刊：
影响因子：
24.5
通讯作者：
Jin, Guangfu
中科院分区：
文献类型：
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作者：
Yan, Caiwang;Zhu, Meng;Jin, Guangfu
目的虽然有一部分基因位点与胃癌的发病风险相关，但其潜在机制尚不清楚。我们的目的是确定新的易感基因，并阐明其在GC发展的机制。设计我们进行了荟萃分析的四个全基因组关联研究（GWAS），包括3771例和5426对照。在靶向测序和功能注释后，我们进行了体外和体内实验，以确认遗传变异体和候选基因的功能。此外，我们从其他五项研究中选择了33个有希望的变异，在7035例病例和8323例对照中进行两阶段复制。结果GWAS的荟萃分析确定了1 q22、5p13.1和10q23.33的3个位点与GC风险相关，p<5×10− 8，并重复了7个已知位点，p<0.05。在5p13.1，rs 59133000 [C]等位基因增强了NF-κB1（核因子κ B亚基1）与PRKAA 1启动子的结合亲和力，导致启动子活性降低和表达降低。PRKAA 1的敲除促进裸鼠中GC细胞增殖和异种移植肿瘤生长。在10q23.33，rs3781266[C]和rs3740365[T]风险等位基因在完全连锁不平衡中分别破坏和创建POU 2F 1和PAX 3的结合基序，导致增加的增强子活性和NOC 3L的表达，而NOC 3L敲低抑制GC细胞生长。此外，位于3q11.2（OR=1.21，p=4.56×10− 9）和4q28.1（OR=1.14，p=3.33×10− 11）的两个新基因座与GC风险相关。结论在中国人群中发现了12个与胃癌发生相关的基因座，并阐明了5p13.1的PRKAA 1和10q23.33的NOC 3L在胃癌发生中的作用机制。
Objective Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development. Design We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies. Results The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10− 8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10− 9) and 4q28.1 (OR=1.14, p=3.33×10− 11) were associated with GC risk. Conclusion We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.